The treatment of systemic lupus erythematosus (SLE), a systemic autoimmune disease that affects many organs such as the joints, skin and kidneys, is based on non-specific immunosuppressive medications that are often ineffective and have very significant side effects. In order to develop more specific less toxic medications, we need a better understanding of the exact steps that lead and then maintain the abnormal autoimmune response in SLE. Recently, a particular T cell subset that expresses the pro-inflammatory cytokine IL-17 has been shown to be present in the kidneys and peripheral blood of patients with SLE. IL-17 producing cells can induce both local inflammation in the target-organs and also help B cells produce antibodies, two of the hallmarks of SLE pathology. In order to assess the role of IL-17 producing T cells in SLE, we used a mouse model of lupus. Indeed, we showed in this pilot study that IL-17 producing T cells accumulate in the spleen and lymph nodes of these mice and also infiltrate their kidneys. We further evaluated the role of IL-17 by culturing lymphocytes from lupus-prone mice in vitro with IL-23, a cytokine that sustains IL-17 responses, and then injected them in healthy but lymphocyte deficient mice. The recipient mice developed lupus-like disease suggesting a pathogenic role of IL-23 induced IL-17 producing T cells. In a different study we generated IL-23 receptor genetically deficient lupus-prone mice. These mice did not develop lupus. Taken together these results led us to hypothesize that IL-23 represents a key mediator of lupus pathogenesis. In this proposal we will test this hypothesis using lupus prone mice and lymphocytes from patients with SLE. Initially, we will test whether treatment of lupus-prone mice with an anti-IL-23 antibody can ameliorate lupus in mice at various stages of their disease course. We will then a. determine the exact source of IL-23 in lupus-prone mice; b. explore the signaling events that lead to the generation and maintenance of IL-17 producing cells in lupus; and c. unravel the mechanisms that IL-17 producing cells use to cause lupus. In the third aim, we will evaluate the role of IL-23 in the generation of pathogenic immune responses by both T and B cells in patients with SLE. These complementary murine and human studies will allow us to understand the role of IL-23 in the development of the abnormal immune response in lupus. The overall goal of this proposal is to provide the necessary rationale to introduce specific biologic agents that interfere with the IL-23/IL-17 pathway in the treatment of patients with SLE.